Background:
Iron deficiency (ID) is a frequent comorbidity in heart failure (HF) associated with adverse outcomes. ESC HF guidelines recommend periodically screening for ID based on serum ferritin and transferrin saturation. Here, we prospectively evaluated a novel method to non-invasively measure erythrocyte zinc protoporphyrin (ZnPP) in patients with HF to detect ID. ZnPP is formed when iron availability is limited and, therefore, divalent zinc (instead of iron) is inserted into protoporphyrin IX, which persists in erythrocytes as an indicator of ID.

Methods:
We enrolled 347 consecutive patients with symptomatic heart failure at Hannover Medical School. ZnPP was optically measured at the lower lip, based on acquisition of fluorescence emission (Homann et al., Nat Commun 2016). For comparison conventional serum-parameters of ID were determined. We stratified HF patients according to ZnPP cutoff value of 70 µmol/mol haem, a value that has previously been proposed to detect ID (Erythrocyte Protoporphyrin Testing; Approved Guideline. C42-A. 1996, Wayne, PA, NCCLS)

Results:
Non-invasive measurement yielded a median ZnPP concentration of 33 [IQR 26-34] µmol/mol haem. The ZnPP concentration was closely related to haemoglobin, serum-ferritin, transferrin saturation (TSAT) and soluble transferrin receptor (sTfR, all p<0,0001). Patients with a ZnPP concentration >70 µmol/mol haem had significantly lower levels of haemoglobin (12,7 [10,9-13,5]) vs 13,7 [12,6-14,8] g/dL) serum-ferritin (72 [32-129] vs 170 [102-289] µg/L), TSAT (15 [10-21] vs 26 [20-33] %) and sTfR (5,0 [2,9-7,8] vs 3,0 [2,4-3,6] mg/L). In addition, patients with a high ZnPP concentration had increased HF severity as indicated by higher circulating concentrations of N-terminal pro-b-type natriuretic peptide (2141 [1218-5458] vs 733 [288-1934] ng/L; p<0,0001) and growth-differentiation factor-15 (2643 [1308-5239] vs 1620 [1073-2525] ng/L; p=0,0015). Notably, in our HF cohort a ZnPP concentration >70 µmol/mol haem had a positive predictive value of 93% for ID, as defined by the recent ESC HF Guidelines.

Conclusion:
In heart failure, ZnPP concentration can be measured with a novel optical method and is strongly related to established markers of systemic iron status and HF severity. This optical method potentially provides a rapid, easy to use means for point-of-care screening for ID in HF.